Diabetes mellitus is a metabolic disease characterized by persistent hyperglycemia (high blood sugar levels). Close monitoring of daily physiological glucose levels reduces the risk of complications caused by conditions such as hypoglycemia or hyperglycemia. This can be achieved by continuous glucose monitoring (CGM) systems, which involve either non-invasive or minimally invasive detection of glucose. Currently, subcutaneously implanted enzymatic electrochemical detection is a prevailing CGM technique, and is the basis for a number of commercially available sensors. These FDA approved commercial products detect glucose by enzyme-catalyzed reactions.
Electrochemical methods are sensitive and specific for glucose detection, but suffer from drawbacks. Firstly, the irreversible consumption of glucose in electrochemical detection induces a potential change in the equilibrium glucose concentration in the tissue, and thus, affects the actual measured glucose level. Furthermore, the rate of glucose consumption can be diffusion limited. Any changes in diffusion layers due to biofouling (e.g., by protein adsorption, cell deposition, and capsule formation) on the sensor surface can affect the diffusion rate, and, thus, the sensor sensitivity. In addition, drift from hydrogen peroxide production and interference from electrode-active chemicals can cause erosion of the sensor electrodes and deactivation of functional enzymes, compromising the sensor accuracy, reliability and longevity. As a result, electrochemical CGM sensors can exhibit large drifts over time, and require frequent calibration by finger pricks. This lack of reliability has been severely hindering CGM applications to practical diabetes management.
To overcome the drawbacks of electrochemical detection, alternative glucose sensing techniques have been investigated. Methods that use non-consumptive, competitive affinity binding of glucose have been considered. One technique exploits the solution of a polysaccharide (e.g., dextran) crosslinked by a glucose-binding protein (e.g., concanavalin A, or Con A): glucose binds competitively to Con A and causes reversible de-crosslinking of the dextran—Con A complex, which can be detected via the resulting changes in solution properties, such as fluorescence or viscosity. As affinity sensing is based on equilibrium binding in which glucose is not consumed, it is not susceptible to electroactive interferents. Also, affinity sensing is considerably more tolerant to biofouling. That is, the deposition of biological material (e.g., cells and proteins) on the implanted affinity sensor surface results only in an increased equilibration time without any changes in measurement accuracy. Consequently, affinity glucose sensors can be highly stable and low-drift.
Unfortunately, Con A is immunogenic and cytotoxic and degrades with time. Although certain alternatives, such as ones utilizing Microelectromechanical Systems (MEMS) technology have been developed, they can suffer from the same or different limitations associated with Con A, e.g., limited mechanical reliability, poor reversibility, and significant drifts. Thus, there remains a need in the art for a sensor for stable and potentially implantable MEMS-based continuous glucose sensing.